Interferons (IFNs) are classified into two distinct groups: type I interferons, including IFNα, IFNβ, IFNτ, and IFNω (also known as IFNαII); and type II interferons, represented by IFNγ (reviewed by DeMaeyer, E., et al., INTERFERONS AND OTHER REGULATORY CYTOKINES, John Wiley and Sons, New York (1988)). Human interferon alpha (HuIFNα) is a type I interferon consisting of approximately 25 known distinct subtypes. These HuIFNαs are highly pleiotropic cytokines with broad-spectrum antiviral, antiproliferative, and immunomodulatory properties. Specifically, they inhibit replication of a variety of RNA- and DNA-containing viruses, inhibit the growth of malignant cells, affect the expression of a variety of oncogenes, and activate natural killer cells.
A subtype of HuIFNα, HuIFNα2, has been used in the treatment of various viral diseases and cancers. However, at the doses required for therapeutic effects, patients often suffer from toxic side effects including “flu-like symptoms”, malaise, anorexia, neutropenia, and abnormal liver function. Many patients cannot tolerate the side effects and treatment with IFNα is discontinued.
Attempts to provide an IFNα that does not cause intolerable side effects have led to development of, for example, hybrid IFNs, consensus IFNα, and long-acting interferons, such as pegylated IFNα. Examples of IFNαs modified with polyethylene glycol (PEG) include the pegylated interferon alpha-2b (PEG lntron®) and alpha-2a (Pegasys®), where 12 kDa polyethylene glycol or a 40 kDa branched-chain PEG chain, respectively, are attached to the INFα.
However, the safety profiles of these PEG-modified IFNαs were qualitatively similar or worse than those of the corresponding native proteins (Bukowski R. M. et al., Cancer, 95(2):389-96 (2002); Bukowski R. M. et al., Journal of Clinical Oncology; 20(18):3841-3949 (2002); Motzer, R. J. et al., J. Clin. Oncol., 19(5):1312-9 (2001); Tong M. J., Journal of Interferon and Cytokine Research, 18:81-86 (1998); Yao G. B. et al., Journal of Gastroenterology and Hepatolog., 15:1165-1170 (2000); Heathcote E. J. et al, N. Engl. J. Med., 343(23):1673-80 (2000); Tong M. J. et al., Hepatology; 26(3):747-54 (1997)). The most commonly reported adverse effects were nausea, anorexia, fatigue and rigors, the incidence of which were dose-related. In addition, with longer duration of therapy, dose-limiting toxicities including severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression were observed at doses of 7.5 μg/kg or higher for PEG Intron® (Bukowski R. M. et al., Cancer, 95(2):389-96 (2002)). Even consensus IFNα at a dose of >9 μg was not tolerated by all patients, and a dose reduction was needed for some patients to complete a study (Yao G. B. et al., Journal of Gastroenterology and Hepatolog., 15:1165-1170 (2000)). Thus, the current pegylated forms of IFNαs and consensus IFNα have failed to address the toxicity problems with IFNα therapy.
There remains a need in the art for an improved polymer modified IFNα that can be used alone and/or in combination with known anti-tumor or anti-viral agents.